Salivary fatty acids in humans: a comprehensive literature review.

Fatty acids (FAs) exert diverse biological functions in humans, influencing physiological responses and, ultimately, health and disease risk. The analysis of FAs in human samples has significant implications and attracts interest in diagnostics and research. The standard method for assessing FA profiles involves the collection of blood samples, which can be inconvenient, invasive, and potentially painful, particularly for young individuals outside hospital settings. Saliva emerged as a promising alternative for evaluating FA profiles in both clinical and research settings. However, to the best of our knowledge, an updated synthesis of the related evidence is unavailable. This comprehensive review aims to summarize data on FA analysis and highlight the potential of the use of salivary FAs as a biomarker in health and disease. Over the past decade, there has been a growing interest in studying salivary FAs in chronic diseases, and more recently, researchers have explored the prognostic value of FAs in acute conditions to check the availability of a non-invasive sampling methodology. A deeper understanding of salivary FAs could have relevant implications both for healthy individuals and patients, particularly in elucidating the correlation between the dietary lipidic content and salivary FA level, Finally, it is crucial to address the standardization of the methods as the sampling, processing, and analysis of saliva are heterogeneous among studies, and limited correlation between blood FAs and salivary FAs is available.

Plasma FA composition in familial LCAT deficiency indicates SOAT2-derived cholesteryl ester formation in humans.

Mutations in the LCAT gene cause familial LCAT deficiency (Online Mendelian Inheritance in Man ID: #245900), a very rare metabolic disorder. LCAT is the only enzyme able to esterify cholesterol in plasma, whereas sterol O-acyltransferases 1 and 2 are the enzymes esterifying cellular cholesterol in cells. Despite the complete lack of LCAT activity, patients with familial LCAT deficiency exhibit circulating cholesteryl esters (CEs) in apoB-containing lipoproteins. To analyze the origin of these CEs, we investigated 24 carriers of LCAT deficiency in this observational study. We found that CE plasma levels were significantly reduced and highly variable among carriers of two mutant LCAT alleles (22.5 [4.0-37.8] mg/dl) and slightly reduced in heterozygotes (218 [153-234] mg/dl). FA distribution in CE (CEFA) was evaluated in whole plasma and VLDL in a subgroup of the enrolled subjects. We found enrichment of C16:0, C18:0, and C18:1 species and a depletion in C18:2 and C20:4 species in the plasma of carriers of two mutant LCAT alleles. No changes were observed in heterozygotes. Furthermore, plasma triglyceride-FA distribution was remarkably similar between carriers of LCAT deficiency and controls. CEFA distribution in VLDL essentially recapitulated that of plasma, being mainly enriched in C16:0 and C18:1, while depleted in C18:2 and C20:4. Finally, after fat loading, chylomicrons of carriers of two mutant LCAT alleles showed CEs containing mainly saturated FAs. This study of CEFA composition in a large cohort of carriers of LCAT deficiency shows that in the absence of LCAT-derived CEs, CEs present in apoB-containing lipoproteins are derived from hepatic and intestinal sterol O-acyltransferase 2.

Pro-resolving and pro-inflammatory fatty acid-derived mediators in sputum of stable state bronchiectasis patients.

BACKGROUND: Bronchiectasis is characterized by neutrophilic inflammation and frequent exacerbations often associated with infections. Lipid mediators play critical roles in the inflammatory response, and the balance between anti-inflammatory and pro-inflammatory mediators could drive to chronic inflammation. The aim of this study was to evaluate the metabolites of docosahexaenoic acid and arachidonic acid in sputum of adults with bronchiectasis defining their associations with clinical data, bacterial load and neutrophil elastase. METHODS: An observational, cross-sectional study was conducted at the bronchiectasis program of the Policlinico Hospital in Milan, Italy, where patients were enrolled. Active neutrophil elastase was measured by enzyme-linked immunosorbent assay, pro-resolving and pro-inflammatory fatty acid-derived mediators were evaluated by mass spectrometry and respiratory pathogens were assessed by real-time PCR. Analysis were performed on sputum collected during stable state and clinical data were also collected. RESULTS: Levels of pro-inflammatory mediators derived from arachidonic acid metabolism showed association with neutrophil elastase, were proportional to Pseudomonas aeruginosa identifications and were linked with radiological gravity index, while the concentrations of pro-resolution mediators derived from docosahexaenoic acid were associated with a better health status, highlighted by the inverse correlation with radiological gravity index, bacterial infections and sputum volume production. CONCLUSION: Pro-inflammatory mediators derived from FA metabolisms are associated with severity of bronchiectasis while DHA-derived metabolites are inversely associated with severity of the disease, which may be used for personized treatment of bronchiectasis.

Whole blood fatty acid profile of young subjects and adherence to the Mediterranean diet: an observational cohort study.

BACKGROUND: Relatively little is known about the physiological whole blood fatty acid composition in young people. Likewise, few studies have addressed the question of correlations between Mediterranean diet (MedDiet) adherence and blood fatty acids in childhood. METHODS: The fatty acid profile in whole blood from subjects, 46 days-19 years old (n = 152), without acute, chronic, or inflammatory diseases was analysed by gas chromatography. Dietary data was extracted from a 24-h recall in a subgroup of subjects (n = 60) into a modified Diet Quality Index for Children (KIDMED) questionnaire to evaluate MedDiet adherence. The cohort was divided into three age groups: < 2, 2- < 10, and 10-19 years. Kruskal-Wallis test and Bonferroni post hoc test were used to check for age group fatty acid differences. For correlations, Spearman's correlation coefficient and partial Spearman's correlation coefficient were used. RESULTS: Linoleic acid, EPA, DHA, palmitic acid, and total saturated fatty acids were stable over age groups. Dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA), total polyunsaturated FAs (PUFA), and total omega-6 PUFA increased from age group < 2 years; alpha-linolenic acid, total omega-3 PUFA, oleic acid, and total monounsaturated FAs decreased. Adherence to the MedDiet was at low-medium level in 91.7% of the subjects. In the age group 2- < 10 yrs., the degree of adherence correlated positively with total MUFA and PUFA balance, negatively with total PUFA, total n6-PUFA, AA/DHA, AA/EPA, and n6/n3. Age did not influence the correlations as to PUFA balance and AA/EPA. CONCLUSIONS: Increased FA proportions with age were seen in the n6-series of PUFA. The n3-FA species decreased or were stable. The vast majority of the subjects with dietary data, 92%, obtained a KIDMED score indicative of low-medium adherence to the MedDiet. The score correlated negatively with various n6-species, i.e. the MedDiet suppressed circulating n6-PUFA. Whole blood may be used to investigate FAs and MedDiet adherence correlations which may be applied in the study of health issues in childhood.

Predictive associations between lifestyle behaviours and dairy consumption: The IDEFICS study.

BACKGROUND AND AIM: Physical activity (PA) and sedentary behaviours (SB) are related to obesity and cardiometabolic risk; however, the literature is controversial regarding the effect of dairy consumption on the development of cardiovascular disease (CVD) risk factors. The aim of this study was to assess longitudinally the relationship between specific lifestyle behaviours (PA and SB) and dairy consumption in a sample of European children and adolescents. METHODS AND RESULTS: Children from the IDEFICS study were included in the analyses. Two measurements, with 2 years' interval, were conducted. A total of 1688 (50.8% boys) children provided information regarding diet, measured by a 24-h dietary recall, PA measured by accelerometers and parent-reported sedentary screen time (SST) at both time points. Different combinations of these behaviours, at each survey and over time, were derived applying specific recommendations. Multilevel ordinal logistic regression and analysis of covariance were used to assess their association with dairy consumption, adjusted for potential confounders. Differences by gender were found regarding dairy product consumption and also adherence to SB and PA recommendations at T0 and T1. Children meeting both lifestyle recommendations, at the two measurement points, had higher probability to consume more milk and yogurt and less cheese than the rest of combinations. CONCLUSIONS: These results suggest that European children with a healthy lifestyle, especially regarding PA and SB over time, consumed more milk and yogurt. This study suggests that the protective effect of specific dairy products found in literature could be partially due to the association of their consumption with specific healthy lifestyles.

Associations of whole blood polyunsaturated fatty acids and insulin resistance among European children and adolescents.

This study aims to examine the association of whole blood n-3 and n-6 polyunsaturated fatty acids (PUFA) with insulin resistance (IR) in children. Whole blood fatty acids were measured in 705 children aged 2-9 years of the European IDEFICS/I.Family cohort using gas chromatography in units of weight percentage of all detected fatty acids (%wt/wt). IR was determined by the Homeostasis Model Assessment for IR (HOMA). Mixed effect models were used to assess the associations between selected baseline PUFA and HOMA z-scores at baseline and after 2- and 6-year follow-ups using models with basic and additional confounder adjustment as well as stratified by sex and weight status. In the basic model, α-linolenic (ß = 1.46 SD/%wt/wt, p = 0.006) and eicosapentaenoic acid (ß = 1.17 SD/%wt/wt, p = 0.001) were positively associated with baseline HOMA z-score. In the stratified analyses, α-linolenic acid was positively associated with HOMA z-score in girls only (ß = 1.98 SD/%wt/wt, p = 0.006) and arachidonic acid was inversely associated with baseline HOMA in thin/normal-weight children (ß = - 0.13 SD/%wt/wt, p = 0.0063). In the fully adjusted model, no statistically significant associations were seen.Conclusions: Our overall results do not indicate a protective role of higher blood n-3 PUFA or an adverse role of higher blood arachidonic acid proportion on the risk of IR. What is Known: •Intervention studies reported a beneficial effect of n-3 PUFA supplementation on insulin resistance compared with placebo while observational studies in cildren are inconclusive. •Studies have shown a positive association of n-6 arachidonic acid and insulin resistance indicating an adverse role of arachidonic acid. What is New: •Cross-sectional and longitudinal analyses based on circulating blood fatty acid concentrations in a large cohort of European children and adolescents. •Overall results do not support a protective role of n-3 PUFA or an adverse role of arachidonic acid in insulin resistance.

Association of desaturase activity and C-reactive protein in European children.

BACKGROUND: Desaturase enzymes influence the fatty acid (FA) composition of body tissues and their activity affects the conversion rate of saturated to monounsaturated FA and of polyunsaturated FA (PUFA) to long-chain PUFA. Desaturase activity has further been shown to be associated with inflammation. We investigate the association between delta-9 (D9D), delta-6 (D6D) and delta-5 desaturase (D5D) activity and high-sensitive C-reactive protein (CRP) in young children. METHODS: In the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) cohort study children were examined at baseline (T0) and after 2 y (T1). D9D, D6D, and D5D activities were estimated from T0 product-precursor FA ratios. CRP was measured at T0 and T1. In a subsample of 1,943 children with available information on FA, CRP, and covariates, the cross-sectional and longitudinal associations of desaturase activity and CRP were analyzed. RESULTS: Cross-sectionally, a D9D increase of 0.01 units was associated with a 11% higher risk of having a serum CRP ≥ Percentile 75 (P75) (OR, 99% CI: 1.11 (1.01; 1.22)) whereas D6D and D5D were not associated with CRP. No significant associations were observed between baseline desaturase activity and CRP 2 y later. CONCLUSION: Cross-sectionally, our results indicate a positive association of D9D and CRP independent of weight status. High D9D activity may increase the risk of subclinical inflammation which is associated with metabolic disorders. As D9D expression increases with higher intake of saturated FA and carbohydrates, dietary changes may influence D9D activity and thus CRP. However, it remains to be investigated whether there is a causal relationship between D9D activity and CRP.

Unsaturated fatty acids, omega-3 index and hospitalization in MISC.

The growing interest in Omega-3 fatty acids as diagnostic markers or new therapeutic approaches also for COVID-19 disease, led us to investigate the presence of potential correlations between Omega-3 fatty acids' levels in whole blood and days of hospitalization or admission to the paediatric intensive care unit (PICU) in 51 children with MIS-C diagnosis following SARS-CoV-2 infection. A statistically significant negative correlation was observed between days of hospitalization and docosapentaenoic acid (22:5n-3,DPA), docosahexaenoic acid (DHA) and total Omega-3 FA levels. Dividing the study group into quartiles according to Omega-3-Index (O3I), no statistically significant difference was observed with respect to the PICU admission rate. In contrast, the number of days of hospitalization in Q4 (O3I ≥ 2.51 %) was different from the number observed in groups Q1-3 (O3I < 2.51 %), with subjects showing higher O3I needing shorter hospitalizations than the subjects with lower O3I. According to previous study investigating O3I in adults affected by Sars-cov-2 we explored the levels of this nutrients in children with MIS-C. Our exploratory study shows that high DPA, DHA and O3I levels could be effective in reducing the length of hospitalization.

Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice.

Spinal and bulbar muscular atrophy (SBMA) is characterized by motor neuron (MN) degeneration that leads to slowly progressive muscle weakness. It is considered a neuromuscular disease since muscle has a primary role in disease onset and progression. SBMA is caused by a CAG triplet repeat expansion in the androgen receptor (AR) gene. The translated poly-glutamine (polyQ) tract confers a toxic gain of function to the mutant AR altering its folding, causing its aggregation into intracellular inclusions, and impairing the autophagic flux. In an in vitro SBMA neuronal model, we previously showed that the antiandrogen bicalutamide and trehalose, a natural disaccharide stimulating autophagy, block ARpolyQ activation, reduce its nuclear translocation and toxicity and facilitate the autophagic degradation of cytoplasmic AR aggregates. Here, in a knock-in SBMA mouse model (KI AR113Q), we show that bicalutamide and trehalose ameliorated SBMA pathology. Bicalutamide reversed the formation of the AR insoluble forms in KI AR113Q muscle, preventing autophagic flux blockage. We demonstrated that apoptosis is activated in KI AR113Q muscle, and that both compounds prevented its activation. We detected a decrease of mtDNA and an increase of OXPHOS enzymes, already at early symptomatic stages; these alterations were reverted by trehalose. Overall, bicalutamide and/or trehalose led to a partial recovery of muscle morphology and function, and improved SBMA mouse motor behavior, inducing an extension of their survival. Thus, bicalutamide and trehalose, by counteracting ARpolyQ toxicity in skeletal muscle, are valuable candidates for future clinical trials in SBMA patients.

Bioequivalence of two omega-3 fatty acid ethyl ester formulations: a case of clinical pharmacology of dietary supplements.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Omega-3 fatty acids are dietary components, present in the body with variable blood concentrations. • Bioavailability evaluations of ethyl ester preparations are hampered by the difficulty in achieving similar concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the preparations being compared. This may require questionable corrections for baseline concentrations. • If repeated doses are given, this may lead to errors because of variable dietary fish intake. If a single dose is selected, this needs to be large, since omega-3 LC-PUFA are present in many compartments. WHAT THIS STUDY ADDS: • We selected subjects with uniform omega-3 background concentrations, to obtain comparable results at the end of treatment. • Testing bioequivalence of two formulations with different EPA : DHA ratios led to single dose intakes of 12 g, which were well tolerated. • In spite of clear differences in EPA : DHA ratios between the two preparations, plasma ratios did not differ and bioequivalence could be well ascertained. AIM: To evaluate the bioequivalence of two omega-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA) ethyl ester preparations, previously shown not to be bioequivalent in healthy subjects, with the objective of providing a guideline for future work in this area. METHOD: A randomized double-blind crossover protocol was chosen. Volunteers with the lowest blood concentrations of n-3 LC-PUFA were selected. They received the ethyl esters in a single high dose (12 g) and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) blood concentrations were analyzed after fingerprick collection at intervals up to 24 h. RESULTS: Differently from a prior study, the pharmacokinetic analysis indicated a satisfactory bioequivalence: for the AUC(0,24 h) 90% CI of the ratio between the two formulations were in the range for bioequivalence (for EPA 0.98, 1.04 and for DHA 0.99, 1.04) and the same was true for C(max) and t(max) (90% CI were 0.95, 1.14 and 1.10, 1.25 for EPA and 0.88, 1.02 and 0.84, 1.24 for DHA). CONCLUSION: This study shows that, in order to obtain reliable bioequivalence data of products present in the daily diet, certain conditions should be met. Subjects should have low, homogeneous baseline concentrations and not be exposed to food items containing the product under evaluation, e.g. fish. Finally, as in the case of omega-3 fatty acids, selected doses should be high, eventually with appropriate conditions of intake.

Differences in fatty acid composition between aquatic and terrestrial insects used as food in human nutrition.

Edible insects may be a source of long-chain polyunsaturated fatty acids (LC-PUFA). The aim of this article is to test for differences in aquatic and terrestrial insects used in human nutrition. We implemented linear models and discovered that differences in the proportion of LC-PUFA between aquatic and terrestrial insects do exist, with terrestrial insects being significantly richer in particular omega-6 fatty acids. In conclusion, any kind of insect may provide valuable sources of LC-PUFA. Because terrestrial insects are more abundant and easier to collect, they can be considered a better source of LC-PUFA than aquatic ones.

Bioactive Compounds in Edible Oils and Their Role in Oxidative Stress and Inflammation.

Diet and inflammatory response are recognized as strictly related, and interest in exploring the potential of edible fats and oils for health and chronic diseases is emerging worldwide. Polyunsaturated fatty acids (PUFAs) present in fish oil (FO), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may be partly converted into oxygenated bioactive lipids with anti-inflammatory and/or pro-resolving activities. Moreover, the co-presence of phenolic compounds and vitamins in edible oils may prevent the development of chronic diseases by their anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory activities. Finally, a high content in mono-unsaturated fatty acids may improve the serum lipid profile and decrease the alterations caused by the oxidized low-density lipoproteins and free radicals. The present review aims to highlight the role of lipids and other bioactive compounds contained in edible oils on oxidative stress and inflammation, focusing on critical and controversial issues that recently emerged, and pointing to the opposing role often played by edible oils components and their oxidized metabolites.

Effects of Mediterranean Diet or Low-Fat Diet on Blood Fatty Acids in Patients with Coronary Heart Disease. A Randomized Intervention Study.

The Mediterranean diet (MD) prevents cardiovascular disease by different putative mechanisms, including modifications in the blood fatty acid (FA) profile. Polytherapy for secondary cardiovascular prevention might mask the effect of MD on the FA profile. This study was aimed to assess whether MD, in comparison with a low-fat diet (LFD), favorably modifies the blood FA profile in patients with coronary heart disease (CHD) on polytherapy. One hundred and twenty patients with a recent history of coronary stenting, randomized to MD or to LFD, completed 3 months of this open-label dietary intervention study. Diet Mediterranean-ness was evaluated using the Mediterranean Diet Adherence Screener (MeDAS) score. Both diets significantly reduced saturated FA (p < 0.01). Putative favorable changes in total n-3 FA (p = 0.03) and eicosapentaenoic acid plus docosahexaenoic acid (EPA + DHA; p = 0.04) were significantly larger with MD than with LFD. At 3 months, in the whole cohort, the MeDAS score correlated inversely with palmitic acid (R = -0.21, p = 0.02), and with palmitoleic acid (R = -0.32, p = 0.007), and positively with total n-3 FA (R = 0.19, p = 0.03), EPA (R = 0.28, p = 0.002), and EPA + DHA (R = 0.21, p = 0.02). In CHD patients on polytherapy, both MD and LFD shift FA blood composition towards a healthier profile, with a more favorable effect of MD on omega-3 levels.

Blood Fatty Acids Profile in MIS-C Children.

MIS-C (multisystem inflammatory syndrome in children) linked to SARS-CoV-2 infection, is a pathological state observed in subjects younger than 21 years old with evidence of either current SARS-CoV-2 infection or exposure within the 4 weeks prior to the onset of symptoms, the presence of documented fever, elevated markers of inflammation, at least two signs of multisystem involvement, and, finally, lack of an alternative diagnosis. They share with adult COVID-19 patients the presence of altered markers of inflammation, but unlike most adults the symptoms are not pulmonary but are affecting several organs. Lipid mediators arising from polyunsaturated fatty acids (PUFA) play an important role in the inflammatory response, with arachidonic acid-derived compounds, such as prostaglandins and leukotrienes, mainly pro-inflammatory and ω3 PUFA metabolites such as resolvins and protectins, showing anti-inflammatory and pro-resolution activities. In order to assess potential alterations of these FA, we evaluated the blood fatty acid profile of MIS-C children at admission to the hospital, together with biochemical, metabolic and clinical assessment. All the patients enrolled showed altered inflammatory parameters with fibrinogen, D-dimer, NT-proBNP, ferritin, aspartate aminotransferase (AST), C-reactive protein (CRP) and TrygIndex levels over the reference values in all the subjects under observation, while albumin and HDL-cholesterol resulted below the normal range. Interestingly, linoleic acid (LA), arachidonic acid (AA) and the ω3 PUFA docosahexaenoic acid (DHA) results were lower in our study when compared to relative amounts reported in the other studies, including from our own laboratory. This significant alteration is pointing out to a potential depletion of these PUFA as a result of the systemic inflammatory condition typical of these patients, suggesting that LA- and AA-derived metabolites may play a critical role in this pathological state, while ω3 PUFA-derived pro-resolution metabolites in these subjects may not be able to provide a timely, physiological counterbalance to the formation of pro-inflammatory lipid mediators. In conclusion, this observational study provides evidence of FA alterations in MIS-C children, suggesting a significant contribution of ω6 FA to the observed inflammatory state, and supporting a potential dietary intervention to restore an appropriate balance among the FAs capable of promoting the resolution of the observed inflammatory condition.

Dairy Consumption at Snack Meal Occasions and the Overall Quality of Diet during Childhood. Prospective and Cross-Sectional Analyses from the IDEFICS/I.Family Cohort.

There is scarce information on the influence of dairy consumption between main meals on the overall diet quality through childhood, constituting the main aim of this research. From the Identification and prevention of Dietary- and lifestyle induced health EFfects In Children and infantS (IDEFICS) study, and based on the data availability in each period due to drop outs, 8807 children aged 2 to 9.9 years from eight European countries at baseline (T0: 2007-2008); 5085 children after two years (T1); and 1991 after four years (T3), were included in these analyses. Dietary intake and the Diet Quality Index (DQI) were assessed by two 24 hours dietary recalls (24-HDR) and food frequency questionnaire. Consumption of milk and yogurt (p = 0.04) and cheese (p < 0.001) at snack meal occasions was associated with higher DQI scores in T0; milk and yogurt (p < 0.001), and cheese (p < 0.001) in T1; and cheese (p = 0.05) in T3. Consumers of milk (p = 0.02), yogurt (p < 0.001), or cheese (p < 0.001) throughout T0 and T1 at all snack moments had significantly higher scores of DQI compared to non-consumers. This was also observed with the consumption of cheese between T1 and T3 (p = 0.03). Consumption of dairy products at snack moments through childhood is associated with a better overall diet quality, being a good strategy to improve it in this period.

Dietary linoleic acid and human health: Focus on cardiovascular and cardiometabolic effects.

This narrative review aims to discuss the more relevant evidence on the role of linoleic acid (LA), a n-6 essential fatty acid that constitutes the predominant proportion of dietary polyunsaturated fatty acids (PUFA), in cardiovascular health. Although LA can be metabolized into Arachidonic Acid (AA), a 20 carbon PUFA which is the precursor of eicosanoids, including some with proinflammatory or prothrombotic-vasoconstrictor action, the large majority of experimental and clinical studies have assessed the potential benefit of increasing dietary intake of LA. Overall, data from clinical studies and meta-analyses suggest an association between high dietary intakes or tissue levels of n-6 PUFA, and specifically LA, and the improvement of cardiovascular risk (mainly of the plasma lipid profile), as well as long-term glycaemic control and insulin resistance. Most observational data show that elevated/increased dietary intake or tissue levels of LA is associated with a reduced incidence of cardiovascular diseases (mainly coronary artery diseases) and of new onset metabolic syndrome or type 2 diabetes. The effects of LA (or n-6 PUFA) in other physio-pathological areas are less clear. High quality clinical trials are needed to assess both the actual amplitude and the underlying mechanisms of the health effects related to dietary intake of this essential fatty acid.

Fish consumption, omega 3 fatty acids and cardiovascular disease. The science and the clinical trials.

Fats in fish and marine animals are rich in highly unsaturated fatty acids (FA with 5 or more double bonds) of the Omega 3 series. These FA, present in aquatic animals as an adaptation to the environmental conditions, reached the human diet through the food chain, with a significant impact on nutrition, life style and cultural conditions. Studies in the 70's showed that high fish consumption is associated with better cardiovascular health and this observation was subsequently confirmed in many studies (epidemiological, cohort, case-control). The evidence is stronger for secondary prevention and when the intakes of fish or omega 3 FA are assessed, rather than just estimated. The major effects are reduction of cardiac, especially sudden, death. Underlying mechanisms concern the antiarrhythmic activities, reduction of thrombotic and inflammatory processes and of serum triacylglycerol levels. In conclusion consumption of fish and its components should be promoted on a global scale especially in the case of subjects with cardiovascular problems. Although still some issues need to be faced especially in large scale interventions (i.e. the assessment of the omega 3 fatty acid status, correlations between levels and cardiovascular indexes and bioavailability of different forms of administration), these recommendations are highly valuable.

Rapid Metabolization of Protectin D1 by ß-Oxidation of Its Polar Head Chain.

Protectin D1 [neuroprotectin D1 (NPD1), PD1] has been proposed to play a key role in the resolution of inflammation. Aside from its ω-monohydroxylated metabolite, little has been reported on its metabolic fate. Upon NPD1 incubation in HepG2 cells, liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed the formation of two main metabolites, identified as 2,3-dinor-NPD1 and 2,3,4,5-tetranor-NPD1 by comparison with standards obtained through demanding total chemical syntheses. These data represent the first evidence of ß-oxidation occurring in specialized proresolving mediators and show that the biotransformation of NPD1 by human hepatoma cells is extremely rapid and faster than that of leukotriene (LTE4). Unlike LTE4, the main metabolic process occurs from the polar head chain of NPD1. It may limit NPD1 systemic circulation and prevent its urinary excretion, making difficult its detection and quantitation in vivo. Interestingly, tetranor-NPD1, but not dinor-NPD1, maintained the bioactivity of the parent NPD1, inhibiting neutrophil chemotaxis in vitro and neutrophil tissue infiltration in vivo.

CHF6001 Inhibits NF-κB Activation and Neutrophilic Recruitment in LPS-Induced Lung Inflammation in Mice.

Inhibitors of phosphodiesterase 4 (PDE4) are potent anti-inflammatory agents, inhibiting the production of inflammatory mediators through the elevation of intracellular cAMP concentrations. We studied the activity of a novel PDE4 inhibitor, CHF6001, both in vitro in human cells and in vivo, using bioluminescence imaging (BLI) in mice lung inflammation. Mice transiently transfected with the luciferase gene under the control of an NF-κB responsive element (NF-κB-luc) have been used to assess the in vivo anti-inflammatory activity of CHF6001 in lipopolysaccharide (LPS)-induced lung inflammation. BLI as well as inflammatory cells and the concentrations of pro-inflammatory cytokines were monitored in bronchoalveolar lavage fluids (BALF) while testing in vitro its ability to affect the production of leukotriene B4 (LTB4), measured by LC/MS/MS, by LPS/LPS/N-formyl--methionyl--leucyl-phenylalanine (fMLP)-activated human blood. CHF6001 inhibited the production of LTB4 in LPS/fMLP-activated human blood at sub-nanomolar concentrations. LPS-induced an increase of BLI signal in NF-κB-luc mice, and CHF6001 administered by dry powder inhalation decreased in parallel luciferase signal, cell airway infiltration, and pro-inflammatory cytokine concentrations in BALF. The results obtained provide in vitro and in vivo evidence of the anti-inflammatory activity of the potent PDE4 inhibitor CHF6001, showing that with a topical administration that closely mimics inhalation in humans, it efficiently disrupts the NF-κB activation associated with LPS challenge, an effect that may be relevant for the prevention of exacerbation episodes in chronic obstructive pulmonary disease subjects.